Cancers, Vol. 10, Pages 69: Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence

Cancers, Vol. 10, Pages 69: Nano-Pulse Stimulation Ablates Orthotopic Rat Hepatocellular Carcinoma and Induces Innate and Adaptive Memory Immune Mechanisms that Prevent Recurrence

Cancers doi: 10.3390/cancers10030069

Authors: Brittany Lassiter Siqi Guo Stephen Beebe

Nano-pulse stimulation (NPS), previously called nsPEFs, induced a vaccine-like effect after ablation of orthotopic N1-S1 hepatocellular carcinoma (HCC), protecting rats from subsequent challenges with N1-S1 cells. To determine immunity, immune cell phenotypes were analyzed in naïve, treated and protected rats. NPS provides a positive, post-ablation immuno-therapeutic outcome by alleviating immunosuppressive T regulatory cells (Treg) in the tumor microenvironment (TME), allowing dendritic cell influx and inducing dynamic changes in natural killer cells (NKs), NKT-cells and T-lymphocytes in blood, spleen and liver. NPS induced specific increases in NKs and NKT-cells expressing CD8 and activation receptors CD314-NKG2D and CD161 (NK1.1) in the TME after treatment, as well as some variable changes in CD4+ and CD8+ effector (Tem) and central memory (Tem) lymphocytes in blood and spleen. After orthotopic challenge, CD8+ T-cells were cytotoxic, inducing apoptosis in N1-S1 cells; additionally, in contrast to post-treatment immune responses, CD4+ and CD8+ memory precursor effector cells (MPECs) and short-lived effector cells (SLECs) were present, while still including CD8+ CD161 NK cells, but not involving CD8+ CD314-NKG2D+ NKs. This immunity was N1-S1-specific and was sustained for at least 8 months. NPS vaccinates rats in vivo against HCC by activating innate and adaptive immune memory mechanisms that prevent HCC recurrence.

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Coccidioidal Meningitis: A Review on Diagnosis, Treatment, and Management of Complications

Abstract

Purpose of review

This article summarizes the diagnosis and treatment of coccidioidal meningitis (CM) and its complications. An overview of current and prospective pharmacologic treatment options and monitoring parameters is provided. A consensus has not been reached regarding universally accepted therapeutic serum levels for azoles because of insufficient evidence. We describe the preferred therapeutic drug level ranges that our institution uses to monitor azole therapy.

Recent findings

Ho et al. described the preparation and administration of intrathecally delivered amphotericin B deoxycholate. Thompson et al. described possible benefits of controversial adjuvant corticosteroid therapy for secondary prevention of vasculitic infarction secondary to CM.

Summary

CM was universally fatal until the advent of intrathecal amphotericin B deoxycholate therapy, the introduction of which changed the natural history of the disease in much the same way as penicillin changed the natural history of bacterial meningitis. Although there was still significant morbidity, survival rates drastically increased to approximately 70%. The introduction of azole therapy has decreased the side effects and burden of treatment but without a significant change in CM-related mortality and morbidity compared with the use of intrathecal amphotericin B deoxycholate therapy.

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The Role of the Sucrose-Responsive IR60b Neuron for Drosophila melanogaster: A Hypothesis

Abstract

In a recent paper, Joseph and colleagues (Joseph et al., 2017) have characterized an IR60b receptor-expressing neuron in Drosophila. They showed that it responds to sucrose and serves to limit sucrose consumption, and proposed that it may thereby act to prevent overfeeding. Here, we propose an alternative hypothesis for the functional role of sucrose feeding control, and for how this limitation of sucrose uptake is accomplished. Adult fruit flies feed by excreting saliva onto the food, and imbibing the predigested liquefied food, or by filling the crop, where the food is predigested. Enzymes in the saliva hydrolyze starch and disaccharides into absorbable monosaccharides. Premature ingestion into the midgut would not give the enzymes in the saliva enough time to predigest the food. Thus, IR60b neurons might serve as a sensor to monitor the digestive state of external food or crop content: when disaccharides (sucrose) concentration is high, ingestion to the gut is inhibited, keeping a low concentration of starch and disaccharides in the midgut.

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Abstracts from the 51th Annual Meeting of the Japanese Association for the Study of Taste and Smell, JASTS-2017, 25–27 September 2017, Kobe International Conference Center, Hyogo, Japan (The president of the meeting was Dr. Mamiko Ozaki, Kobe University)

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Orbital Exenteration in Rhino-Orbito-Cerebral Mucormycosis: A Prospective Analytical Study with Scoring System

Abstract

Mucormycosis is an uncommon, rapidly progressive, angio-invasive, commonly fatal, opportunistic fungal infection. The most critical decision in the management of rhinoorbital mucormycosis is whether the orbit should be exenterated. (1) To layout the indications of orbital exenteration in patients with rhino-orbito-cerebral mucormycosis. (2) To devise a scoring system that predicts the stage at which the exenteration needs to be carried out. A scoring system was devised by a team of experienced Otorhinolaryngologists and Ophthalmologists from prior experience in managing mucormycosis. All patients of mucormycosis visiting our hospital were admitted and included in the study. A total of 15 patients were included. The scoring system is based on 3 main criteria, namely: (1) clinical signs and symptoms. (2) Direct and Indirect Ophthalmoscopy. (3) Imaging. The Sion Hospital Scoring System is an accurate and promising measure to solve the dilemma that is associated with orbital exenteration in orbito-rhino-cerebral mucormycosis.

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Post Earthquake Equilibrium Disturbance: A Study After Nepal–India Earthquake 2015

Abstract

Nepal and adjoining areas of India suffered a series of massive earthquakes in April–May 2015. This was followed by a remarkable increase in the patient presenting with vague dizziness like features which could not be attributed to any defined variant of vestibular disorder. Extensive search of literature revealed only scarce information about ambiguous post-earthquake vestibular symptoms and their management. We performed a detailed epidemiological analysis of these patients to analyse the presentation, underlying mechanism and optimal management. The results were scrutinised in light of existing international literature. We observed that earthquake precipitated a psychological stress like event that provoked features of disequilibrium and the neuroanatomical basis of the proposition was explored. We renounce the hypothesis of Secondary BPPV precipitated by earthquake leading to symptoms. The results were interpreted from the perspective of Indian scenario and its utility in post-earthquake disaster management in our country has been highlighted.

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Mylohyoid motor evoked potentials can effectively predict persistent dysphagia 3 months poststroke

Abstract

Background

The purpose of this study was to investigate the association between mylohyoid motor-evoked potentials (MH-MEP) and swallowing function and determine the value of MH-MEP for predicting aspiration 3 months poststroke.

Methods

Subacute patients within a month of their first stroke were enrolled up for 2 consecutive years. Videofluoroscopic swallowing studies (VFSS) were performed twice. Patients were evaluated during VFSS using the penetration aspiration scale (PAS) and videofluoroscopic dysphagia scale (VDS). MH-MEP was recorded in the mylohyoid muscles. The active electrode was positioned submentally, 2 cm lateral to midline. Magnetic stimulation was performed on the contralateral motor cortex, 2-4 cm anterior and 4-6 cm lateral to the cranial vertex. The resting motor threshold (rMT), latency, and amplitude stimulation at 120% (amp120) and 150% (amp150) of the rMT were assessed. The ratio of each parameter was also estimated. The relationship between MH-MEP and VFSS findings was analyzed.

Key Results

Sixty-eight patients completed the study. On VFSS at 3 months poststroke, 24 (35.3%) patients showed aspiration. The rMT, rMT ratio, amp120 and amp120 ratio were significantly correlated with the PAS and VDS (P < .05). The rMT ratio (OR = 1.208, P = .001) and amp120 ratio (OR = 0.821, P = .002) were independent predictors of aspiration at 3 months. The optimal cut-off value of the rMT ratio was 126.1 (AUC = 0.94, sensitivity = 0.92, specificity = 0.89); that of the amp120 ratio was 66.5 (AUC = 0.89, sensitivity = 0.88, specificity = 0.86).

Conclusions and Inferences

MH-MEP was well-correlated with dysphagia severity assessed by VFSS. The rMT ratio and amplitude ratio of MH-MEP can effectively predict persistent dysphagia 3 months poststroke.

The purpose of this study was to investigate the association between MH-MEP and swallowing function and determine the value of MH-MEP for predicting aspiration three months post-stroke. MH-MEP was well correlated with dysphagia severity assessed by VFSS. The MH-MEP can effectively predict persistent dysphagia 3 months post-stroke.

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The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration

Abstract

Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.

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The impact of sleep quality on the mental health of a non-clinical population

Publication date: Available online 12 March 2018
Source:Sleep Medicine
Author(s): Karine Alexandra Del Rio João, Saul Neves de Jesus, Cláudia Carmo, Patrícia Pinto
IntroductionSleep quality relates to mental health in clinical and non-clinical populations. However, there is more evidence of this relationship in clinical populations. Therefore, there is lack of evidence on how these variables relate and on which sociodemographic factors influence this relationship in non-clinical populations. In this study we hypothesize that in a non-clinical population sleep quality predicts mental health indicators and that age, country and gender moderate this relationship.MethodsIn a sample of 1552 subjects from Portugal, Spain and Brazil, self-reported sleep quality and mental health indicators were assessed through the Pittsburgh Sleep Quality Index and the Depression, Anxiety and Stress Scale-21, respectively. A multivariate linear regression model was used to test the research hypotheses.ResultsThis adjusted model explained 10.1%, 12.3% and 13.1% of the variability of Depression, Anxiety and Stress, respectively, suggesting multiple sources of variance.ConclusionsOur results confirmed that sleep quality predicts mental health in non-clinical populations, and that the variable country is a significant moderator of this relationship.



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Intracranial pressure in patients with papilloedema

Objectives

Papilloedema is a clinical manifestation of chronically raised intracranial pressure (ICP), often seen in idiopathic intracranial hypertension (IIH). However, the extent of intracranial hypertension required to produce papilloedema is not known. We compare ICP values in IIH patients who developed papilloedema and those who did not. We aim to identify a pathological ICP threshold predictive of the development of papilloedema in IIH patients.

Materials and Methods

Single-centre cohort of IIH patients (2006-2016) who underwent 24-hour ICP monitoring (ICPM) and ophthalmology assessments, prior to intervention. Papilloedema was graded according to the Frisén scale. An unpaired t-test compared 24-hour ICPM between papilloedema and no-papilloedema groups. Fisher's exact test was used to determine predictive value of ICP.

Results

Thirty-six patients with IIH (35 F: 1M), mean age 32.5 ± 9.49 years (mean ± SD) were included. Patients with papilloedema had a mean median 24-hour ICP of 10.4 ± 5.32 mm Hg (n = 25), significantly higher than the group without papilloedema 6.31 ± 3.30 mm Hg (n = 11) (P < .05). The papilloedema group were exposed to higher pressures (10 mm Hg) for 30 minutes or more. Using 24-hour median ICP of 10 mm Hg as a minimum cut-off predictive value gives a specificity = 91%, sensitivity = 48%, PPV = 92% and NPV = 44% of detecting papilloedema.

Conclusions

A 24-hour ICP of 10 mmHg or more is a good predictor for papilloedema and reflects a pathological threshold. The range varied widely suggesting papilloedema can occur at even lower pressures. These results are consistent with emerging evidence suggest that pathologically "high" 24 hours ICP is lower than previously quoted.

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Cover Image

The cover image, by Matthias Leonhard et al., is based on the Original Article In vitro biofilm growth on modern voice prostheses, DOI: 10.1002/hed.25053.

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Issue Information

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Targeting mRNA Decapping in AML

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Akihide Yoshimi, Omar Abdel-Wahab
In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.

Teaser

In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3′-to-5′ mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.


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ORY-1001: Overcoming the Differentiation Block in AML

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Prithviraj Bose, Marina Y. Konopleva
In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001—an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)—in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.

Teaser

In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001—an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)—in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.


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A Non-canonical Polycomb Dependency in Synovial Sarcoma

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Joshua J. Waterfall, Paul S. Meltzer
Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state.

Teaser

Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state.


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Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanya Schild, Vivien Low, John Blenis, Ana P. Gomes
Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations that cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype.



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PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Mami Morita, Taku Sato, Miyuki Nomura, Yoshimi Sakamoto, Yui Inoue, Ryota Tanaka, Shigemi Ito, Koreyuki Kurosawa, Kazunori Yamaguchi, Yuki Sugiura, Hiroshi Takizaki, Yoji Yamashita, Ryuichi Katakura, Ikuro Sato, Masaaki Kawai, Yoshinori Okada, Hitomi Watanabe, Gen Kondoh, Shoko Matsumoto, Ayako Kishimoto, Miki Obata, Masaki Matsumoto, Tatsuro Fukuhara, Hozumi Motohashi, Makoto Suematsu, Masaaki Komatsu, Keiichi I. Nakayama, Toshio Watanabe, Tomoyoshi Soga, Hiroshi Shima, Makoto Maemondo, Nobuhiro Tanuma
Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRAS^G12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.

Graphical abstract

Teaser

The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.


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BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P. Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A. Yap, Maureen Hattersley, Mark J. O'Connor, Huawei Chen, Stephen Fawell, Shiaw-Yih Lin, Guang Peng, Gordon B. Mills
Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein). Importantly, BRD4 inhibitor (BRD4i) treatment reversed multiple mechanisms of resistance to PARPi. Furthermore, PARPi and BRD4i are synergistic in multiple in vivo models.

Graphical abstract

Teaser

Sun et al. show that inhibition of BRD4 induces homologous recombination deficiency, through depletion of CtBP, in cells across multiple tumor types and sensitizes them to PARP inhibition. Thus, inhibition of BRD4 reverses resistance to PARP inhibitors and expands the potential use of PARP inhibitors.


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Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Tanmoy Mondal, Prasanna Kumar Juvvuna, Agnete Kirkeby, Sanhita Mitra, Subazini Thankaswamy Kosalai, Larissa Traxler, Falk Hertwig, Sara Wernig-Zorc, Caroline Miranda, Lily Deland, Ruth Volland, Christoph Bartenhagen, Deniz Bartsch, Sashidhar Bandaru, Anne Engesser, Santhilal Subhash, Tommy Martinsson, Helena Carén, Levent M. Akyürek, Leo Kurian, Meena Kanduri, Maite Huarte, Per Kogner, Matthias Fischer, Chandrasekhar Kanduri
Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.

Graphical abstract

Teaser

Mondal et al. show a sense/antisense lncRNA pair expressed from the neuroblastoma (NB) risk-associated 6p22.3 locus is important for retinoic acid-induced NB differentiation gene-regulatory network by controlling CHD7 stability via modulating the cellular localization of the ubiquitin specific protease USP36.


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NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Alexandra Garancher, Charles Y. Lin, Morgane Morabito, Wilfrid Richer, Nathalie Rocques, Magalie Larcher, Laure Bihannic, Kyle Smith, Catherine Miquel, Sophie Leboucher, Nirmitha I. Herath, Fanny Dupuy, Pascale Varlet, Christine Haberler, Christine Walczak, Nadine El Tayara, Andreas Volk, Stéphanie Puget, François Doz, Olivier Delattre, Sabine Druillennec, Olivier Ayrault, Robert J. Wechsler-Reya, Alain Eychène, Franck Bourdeaut, Paul A. Northcott, Celio Pouponnot
Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

Graphical abstract

Teaser

Garancher et al. show that NRL and CRX are master transcriptional regulators of a photoreceptor-specific differentiation program critical for group 3 medulloblastoma (MB) maintenance. They identify BCL-XL as a key NRL target and provide evidence supporting anti-BCL therapy as a strategy for some MB patients.


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Systematic Functional Annotation of Somatic Mutations in Cancer

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta, Zixing Wang, Venkata Hemanjani Bhavana, Richard Tran, Stephanie Soewito, Darlan Conterno Minussi, Daniela Moreno, Kathleen Kong, Turgut Dogruluk, Hengyu Lu, Jianjiong Gao, Collin Tokheim, Daniel Cui Zhou, Amber M. Johnson, Jia Zeng, Carman Ka Man Ip, Zhenlin Ju, Matthew Wester, Shuangxing Yu, Yongsheng Li, Christopher P. Vellano, Nikolaus Schultz, Rachel Karchin, Li Ding, Yiling Lu, Lydia Wai Ting Cheung, Ken Chen, Kenna R. Shaw, Funda Meric-Bernstam, Kenneth L. Scott, Song Yi, Nidhi Sahni, Han Liang, Gordon B. Mills
The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.

Graphical abstract

Teaser

Ng et al. develop a moderate-throughput functional genomic platform and use it to annotate >1,000 cancer variants of unknown significance. The approach is sufficiently sensitive to identify weak drivers, potentially doubling the number of driver mutations characterized in clinically actionable genes.


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Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Yuying Liu, Xiaoyu Liang, Wenqian Dong, Yi Fang, Jiadi Lv, Tianzhen Zhang, Roland Fiskesund, Jing Xie, Jinyan Liu, Xiaonan Yin, Xun Jin, Degao Chen, Ke Tang, Jingwei Ma, Huafeng Zhang, Jing Yu, Jun Yan, Huaping Liang, Siqi Mo, Feiran Cheng, Yabo Zhou, Haizeng Zhang, Jing Wang, Jingnan Li, Yang Chen, Bing Cui, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang
Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8⁺ T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8⁺ T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8⁺ T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.

Teaser

Liu et al. find that tumor-repopulating cells (TRCs) regulate PD-1 expression in CD8⁺ T cells. TRCs secrete kynurenine that is taken up by T cells and activates AhR, which directly regulates PD-1 expression. Blockade of this pathway enhances adoptive T cell therapy efficacy in a mouse melanoma model.


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Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

Publication date: 12 March 2018
Source:Cancer Cell, Volume 33, Issue 3
Author(s): Jaclyn Andricovich, Stephanie Perkail, Yan Kai, Nicole Casasanta, Weiqun Peng, Alexandros Tzatsos
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.

Graphical abstract

Teaser

Andricovich et al. show that KDM6A loss, via aberrant activation of super-enhancers regulating several oncogenes, induces squamous-like, metastatic pancreatic cancer in females. In males, both KDM6A and UTY loss is required to induce squamous-like tumors. Importantly, KDM6A-deficient pancreatic cancer is sensitive to BET inhibitors.


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Association of post-traumatic stress symptom severity with Health-related Quality of Life and self-reported functioning across 12-months after Severe Traumatic Brain Injury

Publication date: Available online 12 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Colin M. Bosma, Nashwa Mansoor, Chiara S. Haller
ObjectiveThe present study investigated the relationship between Post-traumatic stress (PTS) symptom severity and Health-related Quality of Life (HRQoL) after severe Traumatic Brain Injury (TBI).DesignLongitudinal prospective multi-center, cohort study on severe TBI in Switzerland (2007-2011). Injury severity was determined using the Abbreviated Injury Score of the Head region (HAIS), following clinical assessment and initial computed tomography (CT).SettingBaseline data was gathered at time/location of the accident. Longitudinal assessments were done at 3, 6, and 12 months post-injury at the hospital, the rehabilitation unit, and/or the patients living facility.ParticipantsA total of 109 patients with severe TBI were included in the analyses.InterventionsNot applicable.Main Outcome Measurea) HRQoL (SF-12, physical and mental component scales, respectively), b) Self-reported emotional, cognitive, and interpersonal functioning (Patient Competency Rating Scale for Neuro-Rehabilitation [PCRS-NR]).ResultsMultilevel models for patients age >50 and ≤50 respectively, revealed significant negative associations between PTS symptom severity and interpersonal functioning (p≤50 = .002; p>50 = <.001). Among patients ≤ 50 years, PTS symptom severity was significantly associated with total functioning (p = .001) and emotional functioning (p = .0006). Among all patients, PTS symptom severity was significantly associated with cognitive functioning (p = <.001) and mental HRQoL (p = .01).ConclusionFindings indicate that PTS symptoms after severe TBI are negatively associated with HRQoL and emotional, cognitive, and interpersonal functioning.



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Rehabilitation utilization for falls among community-dwelling older adults in the United States in the National Health and Aging Trends Study

Publication date: Available online 12 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Briana L. Moreland, Laura L. Durbin, Judith D. Kasper, Thelma J. Mielenz
ObjectivesTo determine the characteristics of community-dwelling older adults receiving fall-related rehabilitation. Injurious falls cost billions of dollars each year in the United States and these costs are expected to rise. Fall-related rehabilitation can presumably decrease this burden. More needs to be known about the characteristics of older adults utilizing fall-related rehabilitation services.DesignCross-sectional analysis of the fifth round (2015) of the National Health and Aging Trends Study (NHATS). Fall-related rehabilitation utilization was analyzed using weighted multinomial logistic regression with standard errors adjusted for the sample design.SettingIn-person interviews of a nationally representative sample of community-dwelling older adults.Participants7,062 Medicare beneficiaries from NHATS.InterventionsNot ApplicableMain Outcomes MeasuresRehabilitation utilization categorized into fall-related rehabilitation, other rehabilitation, or no rehabilitation.ResultsFall status (single fall OR=2.96, CI: 1.52, 5.77; recurrent falls OR=14.21, CI: 7.45, 27.10), fear of falling (OR=3.11, CI: 1.90, 5.08), poor Short Physical Performance Battery scores (score 0 OR=6.62, CI: 3.31, 13.24; score 1-4 OR=4.65, CI:2.23, 9.68) and hip fracture (OR=3.24 CI: 1.46, 7.20) were all associated with receiving fall-related rehabilitation. Lower education level (less than high school diploma compared to 4-year college degree OR=0.21, CI: 0.11, 0.40) and Hispanic ethnicity (OR=0.37, CI: 0.15, 0.87) were associated with not receiving fall-related rehabilitation.ConclusionHispanic older adults and older adults who are less educated are less likely to receive fall related rehabilitation. Recurrent fallers followed by those who fell once in the past year were more likely to receive fall related rehabilitation than are older adults who have not had a fall in the past year.



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Targeting MDSCs and PD-L1 confers the therapeutic advantage of ablative hypofractionated radiotherapy over conventional fractionated radiotherapy

Publication date: Available online 12 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jie Lan, Rui Li, Li-Mei Yin, Lei Deng, Jun Gui, Bao-Qing Chen, Lin Zhou, Mao-Bing Men, Qiao-Rong Huang, Xian-Ming Mo, Yu-Quan Wei, Bo Lu, Adam Dicker, Jian-Xin Xue, You Lu
PurposeAblative hypofractionated radiotherapy (AHFRT) presents therapeutic advantage over conventional fractionated radiotherapy (CFRT) in primary and oligometastatic cancers, but the underlying mechanisms remain largely unknown. In this study, we compared the immune alterations in response to AHFRT vs. CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT.Experiment Design and ResultsWe established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biological equivalent dose (BED). Compared to CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not in immunocompromised mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors, and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8⁺ T cells. Through the down-regulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGFR signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented a higher efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field.ConclusionTargeting MDSC recruitment and enhancing anti-tumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT is more potent for cancer treatment.

Teaser

This study compared the immune alterations in response to ablative hypofractionated radiotherapy (AHFRT) and conventional fractionated radiotherapy (CFRT) under the same BED, and showed that AHFRT suppressed recruitment of MDSCs into tumors, releasing the inhibition on CD8⁺ T cells, and boosting not only local but also systemic anti-cancer immunity. Adding anti-PD-L1 immunotherapy further boosted the potency of AHFRT. This study extended the mechanisms underlying the efficacy of AHFRT and proposed strategy to combine radiotherapy with immunotherapy.


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Liver Metastatic Melanoma: a Unique Case with Normal Alkaline Phosphatase and Melanuria

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Demodex mites modulate sebocyte immune reaction: Possible role in the pathogenesis of rosacea

Abstract

Rosacea is a common facial skin disorder affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as important. The Demodex mite population in the skin of these patients is significantly higher than in subjects with normal skin suggesting they may be of etiological importance in this disorder. Little is known of the role of these mites in human skin and their potential to interact with the host immune system has not been elucidated.

Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalised SZ95 sebocyte line. Time and mite dose dependent experiments were performed. Direct Demodex effects and the effects of medium in which Demodex had been cultured were evaluated on the TLR-signalling pathway on both a gene and protein expression level.

Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards down modulation of genes in this pathway was observed. A subsequent switch to positive gene up-regulation was recorded after 48 hours of co-culture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced pro-inflammatory cytokine secretion whereas lower numbers did not.

Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalised human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced IL8 secretion by these cells.

This article is protected by copyright. All rights reserved.

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10. Phenotypic variability in motor neuron disease: Site of onset and patterns of disease spread

The clinical heterogeneity across motor neuron disease (MND) is well known, and largely attributed to differences in the relative mix of upper (UMN) and lower motor neuron (LMN) dysfunction, site of onset, and rate of disease progression. These differences hold prognostic significance and clues to patterns of disease spread. Objective understanding of motor dysfunction across these clinical phenotypes is thus pivotal for unravelling disease pathogenesis and mechanisms underpinning disease spread.

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11. Studying human neurophysiology using the mouse tail!

Non-invasive threshold-tracking techniques have been used in vivo to probe the biophysical basis of many neuromuscular conditions in human subjects. However, there are ethical and practical limitations to the study of human subjects, and mouse models provide an alternative and complementary path. Transgenic mouse models and the use of mice during drug development make them attractive targets for axonal excitability studies.

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P04-Spatial geometric analysis in sleep polysomnographic data

The study is devoted to data processing methods in automatic sleep polysomnography (PSG) analysis. The idea is in using covariance matrices a carrier of a discriminative information. In the study, we are challenging with a problem of sleep stage classification. We are trying to solve that problem using spatial geometric analysis. For experiments, we took data from seven patients; data were recorded in National Institute of Mental Health. Artifact-free segments were extracted from the data. The covariance matrix was obtained for each segment.

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21-Brain network activity during reading and writing of Czech words and nonwords

We used fMRI to identify the neural networks involved in processing Czech words and nonwords during reading aloud and writing to dictation. Activation in language areas and domain-general networks - dorsal attention (DAN), frontotparietal control (FPC), and default mode network (DMN) - were compared.

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13. Threshold-tracking TMS without an MEP

Transcranial magnetic stimulation (TMS) is a useful tool for quantifying cortical hyperexcitability in ALS. Short-interval intracortical inhibition (SICI) measures the suppression of descending corticomotoneuronal volleys by GABA-ergic inhibitory interneurons. Threshold-tracking TMS (tt-TMS) studies were developed to overcome the marked variability of motor evoked potentials (MEPs); tt-TMS "tracks" the stimulus intensity required to just evoke a small target MEP. Despite the success of studies using the tt-TMS technique, fasciculations can complicate recordings.

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4. Median/ulnar nerve ultrasound cross-sectional area ratio in ALS

It has been shown that hand muscle wasting in amyotrophic lateral sclerosis (ALS) preferentially affects the thenar muscles, with relative sparing of the hypothenar muscles. This so-called "split-hand" is clinical sign that can be used to differentiate ALS from mimic disorders, and is thought to be caused by a difference in nerve excitability between median and ulnar nerve. The split-hand phenomenon has been largely discussed in regard to neurophysiological finding, but no studies performed comparing median and ulnar nerve size using ultrasound.

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01-High frequency oscillations – A revolution in electroencephalography?

From its very birth in 1924, the clinical electroencephalography (EEG) underwent a relatively smooth evolution, in which the most important milestones have been digitalization and introduction of advanced methods for mathematical analyses of EEG signals. In the clinical practice however, we still evaluate the same curves as Hans Berger did almost one century ago, and their visual analysis remains a gold standard for all the time of EEG method's utilization. Nevertheless, in the last decade we faced a convincing proofs of existence and practical contribution of the piece of information hidden in the EEG curve, about which we had no idea till the of the 20th century.

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25-Influence of vestibular neurectomy on posture of the head and shoulder

The aim of this study was quantitative evaluation of vestibular head tilt in 3 D. Patients after vestibular neurectomy served as model of acute unilateral vestibular failure.

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02-EEG in nonconvulsive status epileptisus (NCSE)

Nonconvulsive status epilepticus (NCSE) is a serious acute situation in neurology which is not always identified. It covers a heterogenous group of electrophysiological situations. The diagnosis of NCSE requires an electroencephalogram (EEG), since clinical signs and symptoms are often nonspecific. As EEG patterns are not always unequivocal, no reliable diagnostic test exists. To simplify the diagnosis, Salzburg EEG Criteria for NCSE were formulated in 2013, with clinical validation still in progress.

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P08-Diffusion kurtosis imaging detects early microstructural changes in dorsal motor nucleus of vagus in intragastric rotenone mouse model of Parkinson’s disease

The aim was to determine whether diffusion kurtosis imaging (DKI-MRI) could detect changes in dorsal motor nucleus of vagus (DMV) in mice who received chronic administration of rotenone. This may help in early diagnosis of patients with Parkinson's disease.Mice received vehicle (VEH) or rotenone (ROT) intragastrically for 4 months. DKI scanning was performed at 2, 3 and 4 months. ROI analysis was used to compare kurtosis and diffusivity parameters in GM regions. WM tracts were investigated using the tract-based spatial statistics.

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03-Falls in temporal lobe epilepsy

Falls are not supposed to be common signs of temporal lobe epilepsy (TLE). The main aim of this study was to identify a group of patients with known history of unexpected falls which could not be explained by presence of ictal asystole or concomitant heart disesase.

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9. Upper motor neuron dysfunction and neuropsychological profile in PLS: Another entrant on the ALS-FTD spectrum

Primary lateral sclerosis (PLS), a rare upper motor neuron disorder, remains a debated entity as an upper motor neuron extreme form of amyotrophic lateral sclerosis (ALS) or a distinct disease. It is now well established that ALS and frontotemporal dementia (FTD) lie on two ends of the frontal neurodegenerative spectrum. While early descriptions of PLS excluded cognitive dysfunction, there is accumulating evidence of varying degrees of frontal lobe deficits accompanying structural and functional changes in the brain in PLS.

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04-Local synchrony in EEG as a marker of epileptogenic zone

Approximately a 1/3 of epileptic patients suffer from pharmacoresistant epilepsy. The surgery is often the only possible treatment, which brings a need for finding epileptogenic zone. The task is intricate in non-lesional patients in whom magnetic resonance imaging is uninformative. Our goal is to find a set of non-invasive imaging methods that would find the epileptogenic zone. We show first results with Local Synchrony (LS) method, that evaluates functional connectivity between cortical areas in short distances.

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23-Prenatal stress, mood, and gray matter volume in young adulthood

This study aimed to determine whether prenatal stress, measured by the number of stressful life events during the first 20 weeks of pregnancy, might relate to mood dysregulation and altered brain structure in young adulthood. Participants included 93 mother – offspring pairs from a community-based birth cohort from the Czech Republic (European Longitudinal Study of Pregnancy and Childhood; ELSPAC-CZ). MRI analyses focused on overall cortical gray matter (GM) volume and GM volume of cortical regions previously associated with major depression.

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05-qEEG predictors of response to antidepressive treatment with ketamine

Time-course of ketamine effect was assessed in depressive patients by QEEG to elucidate changes associated with treatment and to assess potential predictors of response.

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P02-Brain-mapping on animal models

Electroencephalography (EEG) is a method that reflects the electrical activity of the brain. Changes in electrical activity can be reflected also in 2D or 3D maps Measurements of brain electrical activity in animals are essential for the validation of the pharmaco-effect on the brain. The translational approach using similar methods for quantitative EEG needs to be analysed in animal models.We measured nine brains of Wistar rats using dental X-ray. We compared these values with the model from atlas (3d Brain Atlas Reconstructor).

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06-Diagnostic substantiation and current possibilities of VEPS examination

The aim of this introductory lecture is to point out that despite the intensive use of modern imagine techniques (MRI, OCT, etc.), the diagnostic applications of visual evoked potentials (VEPs) need not be obsolete, if not preferable in many cases. This objective, fully non-invasive, low-cost electrophysiological method can detect functional problems of the optic pathway and various brain cortical areas even before a development of the first displayable morphological changes.For the increased sensitivity of VEPs, it is necessary to use a larger spectrum of visual stimuli (activating quite selectively different subsystems of the visual pathway and visual cortex) compared to standards recommended by ISCEV or IFCN.

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P06-Cortical somatosensory processing after botulinum toxin therapy in post-stroke spasticity

In movement disorders, neurophysiology and functional MRI demonstrated abnormalities of sensorimotor processing, responding to peripheral botulinum toxin A (BoNT) treatment. We used Modified Ashworth scale (MAS) to assess spasticity and median nerve somatosensory evoked potentials (SEP) to study changes in sensorimotor cortical areas after BoNT therapy of post-stroke arm spasticity.Seventeen patients (10 men, 7 women, average age 60.2 years) with post-stroke arm spasticity were treated with BoNT into the affected muscles.

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07-Connectivity of the anterior insula differentiates participants with first-episode schizophrenia spectrum disorders from controls: A machine-learning study

Early diagnosis of schizophrenia might reduce the negative impact of the untreated disease. Progressive functional/structural changes were repeatedly detected using classical between-group statistics. However, these findings have been due to their low sensitivity and specificity not clinically useful. Machine learning methods are able to learn from the data and make predictions on the individual level, which might have a diagnostic potential. We performed a classification of patients with the first episode of schizophrenia (FES) and healthy controls (HC) from the resting state functional connectivity (rsFC) and fractional anisotropy (FA) using machine learning on 1:1 age and sex matched samples of 63/63 patients/HC (rsFC) and 77/77 (DTI).

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Contents

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B7-H3 negatively modulates CTL-mediated cancer immunity

Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8⁺ tumor infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8⁺ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8⁺ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8⁺ TILs and recovery of effector function. CD8⁺ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8⁺ T-cells. Compared to a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the anti-tumor reaction. Conclusions:B7-H3 expressed on tumor cells potentially circumvents CD8⁺-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs.

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High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance)

Background: p95HER2 is a truncated form of human epidermal growth factor receptor 2 (HER2) that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Methods: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer overall survival (OS) (hazard ratio [HR]=0.33; P=.002) and decreasing p95HER2 level was significantly associated with longer OS (HR=4.2; P=.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR=0.57; P=.04) whereas p95HER2 level was not (HR= 1.7; P= .25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2= 0.48; P<.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR= 1.7; P= .04) and OS (HR=2.8; P=.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR=1.8; P=.06) and OS (HR=2.3; P=.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies.

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Lipidomic profiling links the Fanconi anemia pathway to glycosphingolipid metabolism in head and neck cancer cells

Purpose:Mutations in Fanconi anemia (FA) genes are common in sporadic squamous cell carcinoma of the head and neck (HNSCC) and we have previously demonstrated that FA pathway depletion in HNSCC cell lines stimulates invasion. The goal of our studies was to use a systems approach in order to define FA pathway-dependent lipid metabolism, and to extract lipid-based signatures and effectors of invasion in FA-deficient cells. Experimental Design: We subjected FA-isogenic HNSCC keratinocyte cell lines to untargeted and targeted lipidomics analyses to discover novel biomarkers and candidate therapeutic targets in FA-deficient cells. Cellular invasion assays were carried out in the presence and absence of N-butyldeoxynojirimycin (NB-DNJ), a biosynthetic inhibitor of the newly identified class of gangliosides, to investigate the requirement of ganglioside upregulation in FA-deficient HNSCC cells. Results: The most notable element of the lipid profiling results was a consistent elevation of glycosphingolipids, and particularly the accumulation of gangliosides. Conversely, repression of this same class of lipids was observed upon genetic correction of FA patient derived HNSCC cells. Functional studies demonstrate that ganglioside upregulation is required for HNSCC cell invasion driven by FA pathway loss. The motility of non-transformed keratinocytes in response to FA loss displayed a similar dependence, thus supporting early and late roles for the FA pathway in controlling keratinocyte invasion through lipid regulation.   Conclusions: Elevation of glycosphingolipids including the ganglioside GM3 in response to FA loss stimulates invasive characteristics of immortalized and transformed keratinocytes. An inhibitor of glycosphingolipid biosynthesis NB-DNJ attenuates invasive characteristics of FA-deficient HNSCC cells.

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Association of p27 and cyclin D1 expression and benefit from adjuvant trastuzumab treatment in HER2-positive early breast cancer: a TransHERA study

Purpose: To assess the prognostic and predictive value of selected biomarkers involved in cell cycle regulation or proliferation in HER2-positive early breast cancer patients. Methods: Protein expression of TOP2A, Ki67, cyclin D1 and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 year; N=561) and observation (N=301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (pre-defined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest. Results: A significant interaction was detected between p27 and treatment (adjusted p=0.0049). Trastuzumab effect was significant in the p27 low subgroup (≤70% p27-positive tumor cells; N=318). HR _{CombTrast vs. Obs} 0.44, 95% CI: 0.29-0.65 (p<0.001). No trastuzumab effect was observed in the p27 high subgroup N=435; HR _{Comb Trast vs. Obs} 0.97, 95% CI: 0.66-1.44, p=0.89), indicating that these patients derived little or no benefit from trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27 high patients experiencing half the hazard of a DFS event compared to low ones (HR _{p27 High vs. Low} 0.49, 95% CI: 0.32-0.75). TOP2A, Ki67 and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit. Conclusions: In TransHERA, HER2-positive early breast cancer patients with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not.

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Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance.

Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR-mutant pre-treatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1 and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1.  Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR=2.4, p=0.015) or MET (HR 3.7, p=0.019), or mutation in TP53 (HR 1.7, p=0.006). In the 136 post-treatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%) and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2914K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo. Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally.

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Activation of the receptor tyrosine kinase AXL regulates the immune microenvironment in glioblastoma

Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NF-κB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with Nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with Nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for GBM patients. Our results suggest that the PROS1-AXL pathway regulates intrinsic mesenchymal signaling as well as the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors.

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RIPK1 binds MCU to mediate induction of mitochondrial Ca2+ uptake and promote colorectal oncogenesis

The receptor-interacting protein kinase 1 (RIPK1) is an essential signaling molecule in pathways for cell survival, apoptosis, and necroptosis. We report here that RIPK1 is upregulated in human colorectal cancer (CRC) and promotes cell proliferation when overexpressed in a colon cancer cell line. RIPK1 interacts with mitochondrial Ca2+ uniporter (MCU) to promote proliferation by increasing mitochondrial Ca2+ uptake and energy metabolism. The ubiquitination site of RIPK1 (RIPK1-K377) was critical for this interaction with MCU and function in promoting cell proliferation. These findings identify the RIPK1-MCU pathway as a promising target to treat CRC.

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Acetylation within the N- and C-terminal domains of Src regulate distinct roles of STAT3-mediated tumorigenesis

Post-translational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions: myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylated an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylated the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activated transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocated into nuclei where it formed the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.

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Do Postpartum Levels of Apolipoproteins Prospectively Predict the Development of Type 2 Diabetes in Women with Previous Gestational Diabetes Mellitus?

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0577-7700

Aims The risk of developing type 2 diabetes is greater in women with previous gestational diabetes mellitus (GDM). Apolipoprotein (Apo) species have been associated with the development of type 2 diabetes in the general population. The aim of this study was to determine if circulating levels of Apo species can predict development of type 2 diabetes in women with previous GDM. Methods Apo AI, Apo AII, Apo B, Apo CII, Apo CIII and Apo E levels were measured in 95 women with normal glucose tolerance, 12 weeks following an index GDM pregnancy. Women were assessed for up to 10 years for the development of type 2 diabetes. Results Postpartum Apo CIII levels, and Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, Apo CIII/Apo E and Apo E/Apo CIII ratios were significantly and positively associated with the development of type 2 diabetes. After controlling for age and BMI, these associations, except for the Apo E/Apo CIII ratio, remained significant. In a clinical model of prediction of type 2 diabetes that included age, BMI, and pregnancy and postnatal fasting glucose, the addition of Apo CIII levels, Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, and Apo CIII/Apo E resulted in a net reclassification improvement of 16.2%. Conclusions High Apo CIII levels and the Apo CIII/Apo AI, Apo CIII/Apo AII, Apo CIII/Apo CII, and Apo CIII/Apo E ratios are all significant risk factors for the development of type 2 diabetes in women with a previous GDM pregnancy.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Frequency of Blood Pressure and Estimated Glomerular Filtration Rate Testing in type 2 Diabetes Mellitus: A Retrospective Study with 43,509 Patients

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0581-4870

Background The goal of this study was to analyze the frequency of blood pressure (BP) and estimated glomerular filtration rate (eGFR) testing in type 2 diabetes mellitus (T2DM) patients followed in general and diabetological practices in Germany. Methods The study included individuals who had at least two concultations due to T2DM diagnosis (ICD-10: E11) between January and December 2016. Patients were followed in 557 general and diabetological practices. The primary outcome was the frequency of BP and eGFR testing in T2DM patients in 2016. The association between several demographic and clinical variables and the odds of receiving≥2 BP and≥1 eGFR tests in the year 2016 was analyzed using multivariate logistic regression models. Results A total of 43,509 individuals were available for analysis. The mean age of the population was 68.6 years (SD=12.4 years). The mean number of measurements was 2.9 (SD=3.5) for BP and 0.4 (SD=1.1) for eGFR. 52.3% of patients were tested at least twice for BP and 15.3% of them at least once for eGFR in 2016. Older patients, individuals followed in diabetological practices, people receiving antihyperglycemic medications, and those affected by chronic conditions (i. e. hypertension, renal complications, or neuropathy) displayed higher odds of receiving≥2 BP and≥1 eGFR tests, whereas patients with a diabetes duration of>1 year displayed lower odds. Conclusions The frequency of BP and eGFR testing was low in T2DM patients in Germany in 2016. Several demographic and clinical variables were associated with this frequency.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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The Effect of Metformin on Serum Gonadotropin Levels in Postmenopausal Women with Diabetes and Prediabetes: A Pilot Study

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0584-0006

Background Metformin was found to decrease serum levels of prolactin and thyrotropin. The aim of this study was to investigate the effect of this drug on hypothalamic-pituitary-ovarian axis activity in postmenopausal women with recently diagnosed and untreated glucose metabolism abnormalities. Methods The study included three matched groups of postmenopausal women: patients with type 2 diabetes (group A, n=16), women with prediabetes (group B, n=14), and individuals with normal glucose metabolism (group C, n=14). Women with diabetes were then treated with high-dose metformin (3 g daily), while women with prediabetes received moderate doses of this agent (1.7 g daily). Glucose homeostasis markers, as well as serum levels of FSH, LH, thyrotropin, prolactin, estradiol and creatinine were measured at baseline and after 16 weeks of metformin treatment. Results In both groups of metformin-treated women, the drug improved glucose homeostasis. High-dose metformin treatment reduced circulating levels of FSH and tended to reduce serum levels of LH, and these effects correlated with an improvement in insulin sensitivity. No changes in gonadotropin levels were observed in prediabetic women receiving moderate doses of metformin. Serum levels of thyrotropin, prolactin and estradiol, as well as the estimated glomerular filtration rate remained at a similar level throughout the study. Conclusions Our study shows that the effect of metformin on hypothalamic-pituitary-ovarian axis activity in postmenopausal women depends on its dose and the magnitude of insulin resistance.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-125324

Background miR-34a is a multifunctional post-translational modulator, which is involved in several diabetes-related complications. However, miR-34a remains to be fully elucidated in the diabetic endothelium from rats. In this study, the role of miR-34a/NOTCH1 signaling in the progression of hyperglycemia-vascular endothelial dysfunction was investigated. Methods In intravenous injection of miR-34a mimics and inhibitors in streptozotocin (STZ)-induced diabetic rats, the biomarkers of endothelial dysfunction was measured. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein levels were assayed by qRT-PCR and western blotting, respectively. Immunohistochemical staining was performed to measure NOTCH1 expression in the diabetic endothelium. Results miR-34a was significantly up-regulated, and NOTCH1 down-regulated, in the thoracic aorta from STZ-induced diabetic rats compared with control group. As compared to model group, the mRNA of NOTCH1 was significantly decreased or increased by miR-34a mimics or inhibitors ex vivo, respectively. Bioinformatics methods further demonstrated that NOTCH1 was a potential target of miR-34a, which was confirmed by dual-luciferase reporter assay. Moreover, both serum ET and NO were significantly increased in diabetic rats as compared to control group. miR-34a inhibitors ex vivo treatment resulted in significant down-regulation ofserum ET and NO levels in diabetic rats as compared to model group. Conclusion These results provide evidence to support the use of miR-34a inhibitors as a therapeutic approach attenuating hyperglycemia-induced vascular endothelial dysfunction.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Levels of Nitric Oxide Metabolites and Myeloperoxidase in Subjects with Type 2 Diabetes Mellitus on Metformin Therapy *

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0577-7776

Introduction Endothelial dysfunction is involved in the pathogenesis of insulin resistance, diabetes mellitus type 2, diabetic complications and preceded clinical manifestation of cardiovascular complications. Increased myeloperoxidase activity has been linked to a number of pathologies with compelling evidence in initiation and progression of inflammatory events. The aim of this study was to compare concentrations of metabolite nitric oxide and myeloperoxidase in the plasma of diabetes mellitus type 2 patients on metformin therapy, without clinical signs of cardiovascular disease and healthy subjects, as well as evaluation of concentrations of analytes in association with glycemic control. Materials and methods Forty four study subjects with diabetes mellitus type 2 and thirty healthy subjects were included in this study. The concentration of myeloperoxidase was determined by enzyme-linked immunosorbent assay, the concentration of nitrate and nitrite with high performance liquid chromatography method. Student's t test, Mann-Whitney U test, Chi-square test and Fisher's exact test were used for statistical analysis. Results The mean concentration of myeloperoxidase was significantly higher in the diabetic group compared to the control group (16.2±4.9 vs. 3.7±1.8; P<0.001).The nitrite concentration was comparable in both groups while the concentration of nitrate was significantly higher in the diabetic group (41.2 [42.9] vs 31.9 [23]; P=0.017). In this study, plasma myeloperoxidase (Spearman's rho=0.421; P=0.004) and nitrate concentration was significantly positively associated with the HbA1c levels while nitrate concentration (Spearman's rho=− 0.308; P=0.047) were was significantly positively negatively associated with the HbA1c levels. Conclusion Concertation of MPO and nitric oxide were significantly increased in a T2DM subject even when on metformin therapy. However, increased concentration of NO strongly correlates with lower levels of HbA1c showing a postive effect of a gylcemic control on endothelial dysfuction. Increased concentrations of NO3- in T2DM subject compared to control, indicates the variety of NO pathways that should be taken into consideration win relation to endothelial function.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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The impact of sleep quality on the mental health of a non-clinical population

Sleep quality relates to mental health in clinical and non-clinical populations. However, there is more evidence of this relationship in clinical populations. Therefore, there is lack of evidence on how these variables relate and on which sociodemographic factors influence this relationship in non-clinical populations. In this study we hypothesize that in a non-clinical population sleep quality predicts mental health indicators and that age, country and gender moderate this relationship.

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Palliative shunt surgery for patients with leptomeningeal metastasis

Publication date: Available online 12 March 2018
Source:Clinical Neurology and Neurosurgery
Author(s): Yuta Murakami, Masahiro Ichikawa, Mudathir Bakhit, Shinya Jinguji, Taku Sato, Masazumi Fujii, Jun Sakuma, Kiyoshi Saito
ObjectivesLeptomeningeal metastasis (LM) is associated with poor prognosis and affects the quality of life (QOL) of end-stage cancer patients. Severe headache associated with hydrocephalus causes reduced QOL. We investigated the clinical value of surgical treatment for hydrocephalus in LM patients.Patients and methodsThe medical records of 11 consecutive patients who underwent lumboperitoneal shunt (LPS) or ventriculoperitoneal shunt (VPS) at our institution between 2007 and 2016 were investigated. Primary brain tumor patients were excluded. We assessed the neurological status and therapeutic effects at 1 month after the shunt surgery.ResultsThe patients were three males and eight females with a median age of 58 years (interquartile range [IR] 52 to 68 years). The median preoperative neutrophil-to-lymphocyte ratio was 6.4 (IR 4.8 to 9.2). Symptom improvement was observed in nine patients, and severe headache was relieved in seven (88%) out of eight patients. The median Karnofsky performance status scale increased from 40 to 60, and the median overall survival after primary malignancy diagnosis was 27.4 months (IR 19.6 to 63.1 months). The median survival after the diagnosis of brain parenchymal metastasis, LM, and shunt surgery were 7.2 months (IR 5.1 to 14.1 months), 3.9 months (IR 3.5 to 6.3 months), and 3.3 months (IR 2.9 to 5.7 months), respectively.ConclusionShunt surgery for hydrocephalus could offer an effective palliative surgical option for symptom relief especially relief of severe headache, contributing improvement of QOL in LM patients.



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Unilateral Cleft Lip Rhinoplasty

Cleft lip rhinoplasty is a challenging procedure both in terms of obtaining desirable appearance and function, but also in achieving consistency across one's patient population. Classically, formal nasal surgery was delayed until the patient had completed nasal and mid-facial growth, however, this paradigm is changing, and more rhinoplasty is being performed at the time of the lip repair which has revolutionized patient outcomes. The three options for repair in terms of timing are designated as primary, intermediate, and secondary (defined later in this text).

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Workforce Considerations, Training, and Diseases in the Middle East

Evaluating and providing global health assistance, humanitarian aid, and medical missions to Middle Eastern countries can be rewarding and challenging. A broad spectrum of financial capabilities supports effective health care delivery and infrastructure. Middle East tension can make obtaining a visa difficult. Personal safety considerations may hinder efforts to develop and carry out clinical and educational programs. Several Middle East countries have sophisticated and modern health care systems. Medical education and specialty training compares with that of Western medicine. The Middle East has a proud heritage as the foundation of many fundamental and modern medical and surgical principles.

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Preserved somatosensory discrimination predicts consciousness recovery in unresponsive wakefulness syndrome

Unresponsive Wakefulness Syndrome (UWS) is a disorder of consciousness (DOC) characterized by spontaneous eye opening in the absence of consistent behavioral responses to external stimuli. When reproducible verbal or motor signs of awareness are detected, the clinical condition is defined as Minimally Conscious State (MCS). In clinical practice, different bedside assessment tools are used to detect purposeful behavior and discriminate between DOCs. Among them, the Coma Recovery Scale-Revised (CRS-R, Kalmar and Giacino, 2005) is considered the most sensitive tool.

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Erratum to: Role of Negative Pressure Therapy as Damage Control in Soft Tissue Reconstruction for Open Tibial Fractures

J reconstr Microsurg
DOI: 10.1055/s-0038-1632386

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Erratum to: Staged Reconstruction (Delayed-Immediate) of the Maxillectomy Defect Using CAD/CAM Technology

J reconstr Microsurg
DOI: 10.1055/s-0038-1635090

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Response letter to the editor about the editorial by oppenheimer and greenberger “baseline asthma burden, comorbidities, and biomarkers in omalizumab-treated patients in PROSPERO” (2017;119:474-5)

In our editorial "Baseline asthma burden, comorbidities, and biomarkers in omalizumab-treated patients in PROSPERO1 regarding the observational study,2 we stated that "the clinician must consider the great cost associated with these agents " referring to omalizumab. A supporting reference3 didn't include indirect costs (absenteeism from school or work, psychologic harms and economic hardships of uncontrolled asthma) although we did mention them. Luskin et al point out that there are indirect benefits from omalizumab that would improve its value (benefits/costs) also known as cost effectiveness ratio.

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A randomized, double-blind, placebo-controlled study of the use of viscous oral cromolyn sodium for the treatment of eosinophilic esophagitis

There is a need for effective, non-steroid pharmacologic therapies for eosinophilic esophagitis (EoE). Cromolyn sodium offers an option as mast cells have been implicated in the symptomatology of EoE and cromolyn has also been shown to have some anti-eosinophilic properties.

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Physiological Recording in the MRI Environment (PRiME): MRI-Compatible Hemodynamic Recording System

Hemodynamic recording during interventional cardiovascular procedures is essential for procedural guidance, monitoring patient status, and collection of diagnostic information. Recent advances have made interventions guided by magnetic resonance imaging (MRI) possible and attractive in certain clinical scenarios. However, in the MRI environment, electromagnetic interference (EMI) can cause severe distortions and artifacts in acquired hemodynamic waveforms. The primary aim of this paper was to develop and validate a system to minimize EMI on electrocardiogram (ECG) and invasive blood pressure (IBP) signals. A system was developed which incorporated commercial MRI compatible ECG leads and pressure transducers, custom electronics, user interface, and adaptive signal processing. Measurements were made on pediatric patients (N = 6) during MRI-guided catheterization. Real-time interactive scanning, which is known to produce significant EMI due to fast gradient switching and varying imaging plane orientations, was selected for testing. The effectiveness of the adaptive algorithms was determined by measuring the reduction of noise peaks, amplitude of noise peaks, and false QRS triggers. During real-time gradient-intensive imaging sequences, peak noise amplitude was reduced by 80% and false QRS triggers were reduced to a median of 0. There was no detectable interference on the IBP channels. A hemodynamic recording system front-end was successfully developed and deployed, which enabled high-fidelity recording of ECG and IBP during MRI scanning. The schematics and assembly instructions are publicly available to facilitate implementation at other institutions. Researchers and clinicians are provided a critical tool in investigating and implementing MRI guided interventional cardiovascular procedures.

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Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline

Publication date: Available online 12 March 2018
Source:Practical Radiation Oncology
Author(s): Benjamin D. Smith, Jennifer R. Bellon, Rachel Blitzblau, Gary Freedman, Bruce Haffty, Carol Hahn, Francine Halberg, Karen Hoffman, Kathleen Horst, Jean Moran, Caroline Patton, Jane Perlmutter, Laura Warren, Timothy Whelan, Jean L. Wright, Reshma Jagsi
IntroductionThe purpose of this guideline is to offer recommendations on fractionation for whole breast irradiation (WBI) with or without a tumor bed boost and guidance on treatment planning and delivery.Methods and materialsThe American Society for Radiation Oncology (ASTRO) convened a task force to address 5 key questions focused on dose-fractionation for WBI, indications and dose-fractionation for tumor bed boost, and treatment planning techniques for WBI and tumor bed boost. Guideline recommendations were based on a systematic literature review and created using a predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength.ResultsFor women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions. The guideline discusses factors that might or should affect fractionation decisions. Use of boost should be based on shared decision-making that considers patient, tumor, and treatment factors, and the task force delineates specific subgroups in which it recommends or suggests use or omission of boost, along with dose recommendations. When planning, the volume of breast tissue receiving >105% of the prescription dose should be minimized and the tumor bed contoured with a goal of coverage with at least 95% of the prescription dose. Dose to the heart, contralateral breast, lung, and other normal tissues should be minimized.ConclusionsWBI represents a significant portion of radiation oncology practice, and these recommendations are intended to offer the groundwork for defining evidence-based practice for this common and important modality. This guideline also seeks to promote appropriately individualized, shared decision-making regarding WBI between physicians and patients.



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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours

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Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression

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From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

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Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials

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Influence of obesity-related risk factors in the aetiology of glioma

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Gordon Fordyce 1925–2018

Gordon Fordyce, a former Consultant Oral Surgeon and President of the British Association of Oral Surgeons, passed away on February 18th.

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Relation between globus pharyngeus and OSA in patients examined simultaneously by PSG and pH monitor: A cross sectional study

This was a first cross-sectional single-center study to research the relation between globus pharyngeus, OSA and GERD. Since previous clinical studies have demonstrated a relationship between globus phayrngeus and GERD, however, no reported study on the relation between globus pharyngeus, sleep disorders including OSA, and GERD.

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Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma

Future Oncology, Ahead of Print.


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Does sarcopenia affect outcome in patients with non-small-cell lung cancer harboring EGFR mutations?

Future Oncology, Ahead of Print.


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IFN-α in advanced well-differentiated neuroendocrine tumors: the neglected drug?

Future Oncology, Ahead of Print.


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Comparison of primary breast cancer and paired metastases: biomarkers discordance influence on outcome and therapy

Future Oncology, Ahead of Print.


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Different inhibitors for the same target in metastatic luminal breast cancer: is there any difference?

Future Oncology, Ahead of Print.


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Utilization of radiotherapy and stereotactic body radiation therapy for renal cell cancer in the USA

Future Oncology, Ahead of Print.


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Triple negative breast cancer: are we scoring a home run?

Future Oncology, Ahead of Print.


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Successfully Managing Impending Skin Necrosis following Hyaluronic Acid Filler Injection, using High-Dose Pulsed Hyaluronidase

Summary: Facial fillers are becoming increasingly popular as aesthetic procedures to temporarily reduce the depth of wrinkles or to contour faces. However, even in the hands of very experienced injectors, there is always a small possibility of vascular complications like intra-arterial injection of filler substance. We present a case report of a patient who developed features of vascular obstruction in right infraorbital artery and tell-tale signs of impending skin necrosis, after hyaluronic acid filler injection by an experienced injector. The diagnosis of a vascular complication was made quickly with the help of clinical features like blanching, livedo reticularis, and poor capillary refill. Patient was treated promptly with "high-dose pulsed hyaluronidase protocol" comprising three 1,000-unit pulses of hyaluronidase, administered hourly. There was no further increase in size of the involved area after the first dose of hyaluronidase. All of the involved area, along with 1 cm overlapping in uninvolved skin area, was injected during each injection pulse, using a combination of cannula and needle. Complete reperfusion and good capillary filling were achieved after completion of 3 pulses, and these were taken as the end-point of high-dose pulsed hyaluronidase treatment. Immediate skin changes after filler injections, as well as after hyaluronidase injections and during the 3-week recovery period, were documented with photographs and clinical notes. Involved skin was found to have been fully recovered from this vascular episode, thus indicating that complete recovery of the ischemic skin changes secondary to possible intra-arterial injection could be achieved using high-dose pulsed hyaluronidase protocol.

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Minimally Invasive Face Lifting and Lipofilling

No abstract available

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Drug May Help Prevent Resistance to Toxin-Based Leukemia Therapy

A new study has identified a possible strategy for improving the efficacy of a toxin-based cancer treatment, moxetumomab pasudotox, in some patients with acute lymphoblastic leukemia (ALL).

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Monopolar radiofrequency ablation of thyroid nodules: a prospective Austrian single center study.

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Monopolar radiofrequency ablation of thyroid nodules: a prospective Austrian single center study.

Thyroid. 2018 Feb 28;:

Authors: Dobnig H, Amrein K

Abstract
Background Monopolar radiofrequency ablation is currently deemed an exotic treatment option for benign thyroid nodules in many central European countries. The aim of this study was to prospectively evaluate safety and efficacy of this method in a large patient cohort following its introduction in Austria. Patients and methods Peri- and post-interventional complications were analyzed for 277 patients. Efficacy was determined for 300 and 154 nodules at, respectively, 3 and 12 months post-treatment. All treatments were performed with an internally-cooled 18G radiofrequency electrode using a free-hand, so-called "moving-shot" technique following subcutaneous and local perithyroidal anesthesia. Results Mean patient age (SD) was 52±12.9 years (75% female) and overall mean baseline nodule volume (SD) was 13.8±15.9 ml. 62.8% of patients had visible nodules, 40% a symptom score ≥4 on a 10-point visual analogue scale and 14.4% hyperthyroidism. Mean overall nodule volume reduction rates (VRR) at 3 and 12-months were, respectively, 68±16% and 82±13% (all P<0.001). At 12 months, 81% of nodules exhibited a VRR of ≥70%, with 10, 6 and 2% of nodules showing VRRs of, respectively, 60-70, 50-60 and ≤50%. Subgroup analysis according to baseline nodule size (≤10 ml to >30 ml) or baseline nodule composition (solid, mixed, cystic), revealed significantly higher VRRs for smaller and cystic nodules. Nodule shrinkage was, moreover, accompanied by significantly improved symptom and cosmetic scores after 3 and 12 months (all P<0.001). Of 32 hyperthyroid patients, 27 were euthyroid (84%), 4 had subclinical hyperthyroidism and one subclinical hypothyroidism at last follow-up. Post-procedural complications were absent in 83% of patients, minimal in 12.9%, moderate and reversible in 3.2% (1.8% voice change, 0.7% hyperthyroidism, 0.3% wound infection treated with antibiotics, 0.3% epifascial hematoma) and irreversible in 0.7% (one case with hypothyroidism and one with a wound infection treated by surgery). Conclusions We conclude that a single treatment course with monopolar RFA is both safe and highly effective in terms of nodule volume reduction, relief of local symptoms and (in patients with hyperthyroidism) restoration of euthyroid function. In no case was a prescription of thyroid medication required amongst those patients that were euthyroid at baseline.

PMID: 29490593 [PubMed - as supplied by publisher]

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A Single Radioactive Iodine Treatment has a Deleterious Effect on Ovarian Reserve in Women with Thyroid Cancer: Results of a Prospective Pilot Study.

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A Single Radioactive Iodine Treatment has a Deleterious Effect on Ovarian Reserve in Women with Thyroid Cancer: Results of a Prospective Pilot Study.

Thyroid. 2018 Feb 21;:

Authors: Yaish I, Azem F, Gutfeld O, Silman Z, Serebro M, Sharon O, Shefer G, Limor R, Stern N, Tordjman KM

Abstract
BACKGROUND: Women of reproductive age with differentiated thyroid cancer (DTC) often need to receive radioactive iodine (RAI) treatment after surgery. In contrast to the well documented effect of RAI on testicular function, the potential negative effects of this treatment on ovarian reserve have been largely dismissed. The objective of this pilot study was to examine the possibility that RAI treatment is deleterious to the ovarian reserve by prospectively measuring the concentration of anti-Müllerian hormone (AMH) after this treatment.
METHODS: Thirty premenopausal women (aged 34 years, range 20-45) with a new diagnosis of DTC scheduled to undergo RAI ablation were recruited for this study. All of them had TNM stage 1 disease (T1-3, N0 or N1, M0), and were scheduled to receive RAI doses ranging from 30-150 mCi. AMH was measured at baseline, and 3, 6, 9 and 12 months after the administration of RAI.
RESULTS: Of the 30 women, only 24 returned after the baseline assessment. RAI treatment resulted in a significant decrease in AMH concentrations at 3 months, from 3.252.75 to 1.91.74 ng/ml, P<0.0001. Only partial recovery was subsequently documented, 82% of subjects had final values below baseline levels, such that at one year serum AMH was still 32% lower than prior to treatment (2.361.88 ng/ml, P<0.005). The only two continuous variables that correlated with the extent of AMH reduction at 3 months were the woman's age (r=0.51, P=0.02), and the age at menarche (r=0.48, P=0.03). Importantly, the RAI dose was not associated with the extent of AMH reduction, neither were smoking, nor the use of birth control pills. Older (>35) subjects were significantly more likely to experience a marked AMH reduction at 3 months (63.7±18.5% vs 33.1± 29.2%, P=0.01). The only predictor of recovery after 1 year was the extent of AMH decrease at 3 months: the lower the decline, the higher the chances for recovery.
CONCLUSIONS: RAI in DTC has a rapid and profound effect on ovarian reserve with only a partial recovery potential. In an era of declining human fertility, RAI should be carefully planned in women of reproductive age. AMH measurement could be used as a tool in this decision-making process.

PMID: 29466932 [PubMed - as supplied by publisher]

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